Human hepatocellular carcinoma is a common disorder which carries a poor prognosis. Since many hepatomas arise in patients with existing liver disease, liver transplantation seems to be a logical therapy. Unfortunately, the survival rates have been dismal. The major reason for failure is tumor recurrence, either from unrecognized metastatic disease already present at the time of operation (subclinical metastatic disease), or from newly metastatic disease which may be related to manipulation of the host liver at the time of transplantation. A strategy to prevent recurrent disease would involve administering an adjunctive agent that is toxic to the hepatoma cells prior to transplantation. The administered toxin would kill any subclinical metastatic hepatoma cells as well as potential metastatic cells related to the primary tumor. Although there are known toxins which are effective in killing hepatoma cells, they are not specific and result in the death of normal hepatocytes with subsequent liver failure. The absence of selectivity of chemotherapeutic agents in the proposed treatment plan is overcome by liver transplantation. The idea of using combinations of hepatotoxins to kill hepatomas has been explored by Weber, et.al., using the concept of enzyme pattern directed chemotherapy to increase the specificity of toxins for tumor. To protect normal hepatocytes from the administered hepatotoxins, Wu, et.al., have used the approach of receptor mediated rescue, taking advantage of receptors that are expressed on normal hepatocytes, but not on tumors. These receptors can be utilized to facilitate uptake of a protective antidote to the administered toxin. Our proposed therapy will utilize combinations of hepatotoxins suggested by Weber to kill hepatoma cells, while liver transplantation will be used to rescue damaged normal hepatocytes. Our preliminary results indicate that both rat hepatomas and human hepatomas are susceptible in vitro to galactosamine, the prototypic hepatotoxin. We have established a reproducible rat model of metastatic hepatocellular carcinoma, and have demonstrated that orthotopic liver transplantation is feasible in rats receiving lethal, hepatotoxic doses of galactosamine. In addition, we have demonstrated that our proposed therapy has an effect on decreasing the incidence of metastatic tumors. We plan to test the proposed therapeutic approach in several different in-vitro and in-vivo systems. Initial experiments will utilize a syngeneic transplant system with no postoperative immunosuppression. Later experiments will evaluate the effect of immunosuppression on tumor recurrence following this treatment protocol in an allogeneic rat transplant system. Eventual work will focus on the applicability of this treatment concept to established human hepatoma cell lines and cells from surgical resection specimens. Tumor cells will initially be tested in- vitro for susceptibility to hepatotoxic agents. The nude rat will ultimately serve as a liver transplant model to evaluate the treatment protocol in an in-vivo system with human hepatoma cells.
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| Freise, C E; Liu, T; Ascher, N L et al. (1996) Hepatotoxins and liver transplantation decrease pulmonary metastases in rats with hepatoma. J Surg Res 64:198-202 |
